US2024376082A1PendingUtilityA1

Pyridinyl substituted oxoisoindoline compounds

Assignee: BRISTOL MYERS SQUIBB COPriority: Apr 6, 2021Filed: Jun 25, 2024Published: Nov 14, 2024

Est. expiryApr 6, 2041(~14.7 yrs left)· nominal 20-yr term from priority

Inventors:Yan Chen Godwin Kwame Kumi Audris Huang Satheesh Kesavan Nair Bharat Dinkar Shimpukade Suresh Babu Vishwa Krishna Penmetsa James Aaron Balog

A61P 35/00A61P 31/12A61K 31/4545C07D 401/14

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References

Claims

Abstract

Disclosed are compounds of Formula (I):or a salt thereof, wherein R1, R2, R4, R6, m, and n are defined herein. Also disclosed are methods of using such compounds to inhibit Helios protein, and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of viral infections and proliferative disorders, such as cancer.

Claims

exact text as granted — not AI-modified

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         R 1  is —NH 2  or —NH(CH 3 ); 
         each R 2  is independently F, Cl, —CN, C 1-4  alkyl, —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , or cyclopropyl; 
         each R 4  is independently F, Cl, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , or —OCH 3 ; 
         R 6  is hydrogen, C 1-2  alkyl, or C 1-2  fluoroalkyl; 
         m is zero, 1, 2, or 3; and 
         n is zero, 1, 2, or 3; 
         with the proviso that when R 6  is hydrogen, m is 1, 2, or 3. 
       
     
     
         2 . The compound according to  claim 1  or a salt thereof, wherein R 1  is —NH 2 . 
     
     
         3 . The compound according to  claim 1  or a salt thereof, wherein R 1  is —NH(CH 3 ). 
     
     
         4 . The compound according to  claim 1  or a salt thereof, wherein each R 2  is independently F, —CN, —CH 3 , or —CF 3 . 
     
     
         5 . The compound according to  claim 1  or a salt thereof, wherein R 6  is C 1-2  alkyl, —CH 2 F, —CF 2 H, —CF 3 , or —CH 2 CF 3 . 
     
     
         6 . The compound according to  claim 1  or a salt thereof, wherein R 6  is —CH 3 . 
     
     
         7 . The compound according to  claim 1  or a salt thereof, wherein:
 R 6  is C 1-2  alkyl, —CH 2 F, —CF 2 H, —CF 3 , or —CH 2 CF 3 ; and 
 m is zero. 
 
     
     
         8 . The compound according to  claim 1  or a salt thereof, wherein:
 R 6  is —CH 3 ; and 
 m is zero. 
 
     
     
         9 . The compound according to  claim 1  or a salt thereof, wherein each R 4  is independently F, —CH 3 , —CHF 2 , or —CF 3 . 
     
     
         10 . The compound according to  claim 1  or a salt thereof, wherein:
 each R 4  is F, —CH 3 , —CHF 2 , or —CF 3 ; 
 R 6  is hydrogen; and 
 m is 1 or 2. 
 
     
     
         11 . The compound according to  claim 1  or a salt thereof, wherein:
 each R 4  is F or —CH 3 ; 
 R 6  is hydrogen; and 
 m is 1 or 2. 
 
     
     
         12 . The compound according to  claim 1  or a salt thereof, wherein:
 R 4  is F or —CH 3 ; 
 R 6  is hydrogen; and 
 m is 1. 
 
     
     
         13 . The compound according to  claim 1  or a salt thereof, wherein said compound is:
 2-amino-6-(2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (1); 
 2-amino-6-(2-(2,6-dioxopiperidin-3-yl)-6-methyl-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (2); 
 2-amino-6-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (3); 
 3-(5-(6-amino-4-methylpyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (4); 
 3-(5-(6-amino-4-(trifluoroethyl) pyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (5); 
 3-(4-fluoro-5-(4-methyl-6-(methylamino)pyridin-2-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione (6); 
 3-(5-(6-amino-4,5-dimethylpyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (7); 
 3-((S)-5-(6-amino-4,5-dimethylpyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (8); 
 3-((R)-5-(6-amino-4,5-dimethylpyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (9); 
 2-amino-6-((3S)-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (10); 
 2-amino-6-((3R)-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (11); 
 3-((S)-5-(4,5-dimethyl-6-(methylamino)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (12); 
 3-((R)-5-(4,5-dimethyl-6-(methylamino)pyridin-2-yl)-3-methyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (13); 
 6-((3S)-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-5-yl)-4-methyl-2-(methylamino) nicotinonitrile (14); 
 6-((3R)-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-5-yl)-4-methyl-2-(methylamino)nicotinonitrile (15); 
 3-((S)-5-(6-amino-4,5-dimethylpyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (16); 
 3-((R)-5-(6-amino-4,5-dimethylpyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (17); 
 3-(5-(6-amino-3-methylpyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (18); 
 3-(5-(6-amino-5-fluoro-4-methylpyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (19); 
 3-(5-(6-amino-3-fluoro-4-methylpyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (20); 
 3-(5-(6-amino-5-fluoro-4-methylpyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (21-22); 
 2-amino-6-((3R)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-methyl-1-oxoisoindolin-5-yl)-4-methylnicotinonitrile (23); 
 3-((R)-5-(6-amino-4-methylpyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (24); 
 3-((R)-5-(6-amino-4-(trifluoromethyl) pyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (25); 
 3-((R)-5-(6-amino-3-methylpyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (26); 
 3-((R)-5-(6-aminopyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl) piperidine-2,6-dione (27); 
 (R)-3-((R)-5-(6-amino-4,5-dimethylpyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione 28); 
 3-((R)-5-(6-amino-5-fluoro-4-methylpyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (29); or 3-((S)-5-(6-amino-5-fluoro-4-methylpyridin-2-yl)-4-fluoro-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30). 
 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         15 . A method for the treatment of cancer, in a patient comprising administering to said patient a therapeutically effective amount of a compound and/or pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         16 . The use of  claim 15 , wherein said cancer is selected from cancer of the colon, gastric, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia and melanoma. 
     
     
         17 . A method of decreasing Helios protein levels, Helios activity level, or Helios expression level in the cells comprising contacting said Helios protein with a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method according to  claim 17 , wherein Helios protein is the amino acid sequence encoded by SEQ ID NOs: 1, 2, 3, 4, or 5. 
     
     
         19 . A method of decreasing Eos protein levels, Eos activity level, or Eos expression level in the cells comprising contacting said Eos protein with a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method according to  claim 19 , wherein Eos protein is the amino acid sequence encoded by SEQ ID NOs: 7 or 8.

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